Tissue repairis accompanied by an ordered sequence of cellular responses which leads to a clearly defined sequence of alterations in the context and function of the wound fluid comprising the extracellular environment. There is a gradual accumulation of all amino acids with the exception of arginine, a decrease in glucose, and an increase in lactate concentration. Specific temporal alterations occur in the expression of message for peptide growth factors, and classical endocrine hormones accumulate to reach concentrations far exceeding those found in plasma. Previous studies support the concept that wound metabolism and wound cell function are independent of circulating hormone and substrate alterations. Yet several of the more common clinical examples of impaired wound healing involve systemic hormonal, and substrate changes. This proposal will examine this apparent controversy, attempt to understand the lack of hormonal responsiveness in normal wound healing, and investigate the underlying mechanisms where pathological alterations of hormone and substrate concentrations are associated with poor repair. Two hypotheses are presented: first, that under normal circumstances the wound environment is insensitive to circulating hormone concentrations; second, that the impaired wound healing associated with pathologic changes in systemic hormonal substrate concentrations is due to nonclassical effects of these hormones or substrates.